This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Alpha-synuclein (aS) is a highly conserved presynaptic protein that participates in synaptic strength maintenance and dopamine homeostasis. It is also involved in regulation of intracellular dopamine levels at several points of control. However, accumulation of aS amyloid fibrils was implicated as the hallmark in the development of Parkinson's disease. The three single-point mutations in a-synuclein, namely, A30P, A53T, and E46K, (as well as a triplication of the aS gene) have been linked to a rare familial form of Parkinson's disease (PD). On the other hand the vast majority of Lewy body-related disease cases is sporadic and involves the wild type of aS. Normal functions of [unreadable]S involve protein-membrane interactions upon which the protein undergoes transformations from a disordered structure in cytosol to the highly helical one in membrane-bound state. In several completed subprojects we have successfully applied Pulsed dipolar ESR to characterize the behavior of wild type aS bound to SDS micelles and phospholipid membranes [1, 2]. In our detailed study on the structural properties of WT and PD-linked mutants A30P, E46K and A53, we showed that all variants of aS posses the propensity to switch between broken and extended helix conformations, depending on aS environment [1-3]. Yet, there is insufficient information about the factors that trigger and govern the aggregation of this protein. Therefore, we undertook a study that has as its goal to learn whether and how the interaction with the common membrane mimetics, such as SDS, could initiate the aggregation of aS. So far, we have studied the interaction with SDS of single spin-labeled cysteine mutants of aS. [1] Borbat, P.;Ramlall, T. F.;Freed, J. H.;Eliezer, D. J. Am. Chem. Soc., 2006, 128, 10004-10005. [2] Elka R. Georgieva, Trudy F. Ramlall, Peter P. Borbat, Jack H. Freed, David Eliezer, J. Am. Chem. Soc. 2008, 130, 12856-12857. [3] E.R. Georgieva, T.F. Ramlall, P.P. Borbat, J.H. Freed, D. Eliezer, J Biol Chem, 285 (2010) 28261-28274.